Comparative study of the reactions of dilithiated vicinal diesters and

Mar 8, 1982 - Kevin G. Bilyard,' Peter J. Garratt,* Roger Hunter, and Ester Lete. Department of Chemistry, University College London, London WCIH OAJ,...
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J. Org. Chem. 1982,47,4131-4136

4731

Comparative Study of the Reactions of Dilithiated Vicinal Diesters and Dilithiated l,%-Dicarboximideswith Methyl Iodide, a,w-Dihalides, a,w-Ditosylates, and w-Bromo Esters Kevin G. Bilyard,' Peter J. Garratt,* Roger Hunter, and Ester Lete Department of Chemistry, University College London, London WCIH OAJ, England

Received March 8, 1982 The reactions of dilithiated dimethyl cyclohexane-l,2-dicarboxylate(l),dimethyl 4-cyclohexene-1,2-dicarboxylate

(Z),N-substituted cyclohexane-1,Z-dicarboximides1 la-c,and N-phenyl-4-cyclohexene-1,Z-dicarboximides 18 with a variety of substrates have been investigated and the results compared. Intramolecular reactions of the monolithiated esters prevent complete conversion to the dilithiated species, but this problem is circumvented in the case of the carboximides which form the dilithiated species quantitatively. The dilithiated species 1 undergoes equilibrium with ethanal or propanone to give monoacylated products formed by intramolecular reactions. Annelation of both 2 and 18 occurs with ethyl 4-bromobutyrate under the appropriate conditions, but in the latter case the carboximide ring undergoes considerable cleavage, presumably in a release of strain. Equilibration of 2 and the w-bromo ester occurs at higher temperatures,and rearrangedproducts result. The conditions necessary for successful annelation of a 1,2-disubstituted dianion are described. The 13C NMR spectrum of dilithiated N-tert-butylcyclohexane-1,2-dicarboximideis reported and adduced as evidence for the pyrrole-like structure

lla.

We have earlier shown that the treatment of vicinal diesters with lithium diisopropylamide (LDA) gives species which react as dianions and which can be annelated with diethyl phthalate2 and with a,o-dihalides and -dito~ylates.~ The yields in these reactions seldom exceeded 60% although little or no other ether-soluble product could be detected. Since the yields were also nonquantitative in the simple dialkylation of these lithiated species with methyl iodide, it was decided to investigate this anomoly by conducting a careful product balance on the reaction of the dilithiated esters 1 and 2 with methyl iodide. Be-

Scheme I

\ OMe

I

OMe

8

7

Scheme I1 C02Me

+

CH3CRO

e

CO2Me

1

3

a + C02Me

C02Me

5

9a, R =

2

4

H

b, R = CH, 6

sides the dimethylated derivatives 3 and 4, isolated in 55% and 65% yields, respectively, the half esters 5 and 6 were obtained from the aqueous phase in yields of 28% and 22%. The formation of 5 and 6 could be most readily accounted for by the elimination of methoxide ion from the dianion to give a ketene intermediate which would then hydrate to the acid during isolation. However, if this were the case, then the dianion should be unstable, decomposing with the loss of lithium methoxide. In fact, the dilithiated species, once formed, are extremely stable, and the yields of methylated product remain unchanged even when solutions of the dianions are stored at ambient temperatures for a number of hours. The half-ester may be formed from the monolithiated diester 7: attack by the oxygen of the enolate anion on the adjacent ester group with elimination of methoxide would give the methoxy lactone 8, which would be susceptible to ready hydrolysis (Scheme I). An attempt to substantiate the mechanism outlined in Scheme I by preparation of the monolithiated species was (1) Smith, Kline and French Research La., The Frythe, Welwyn, Herb AL6 9AR, United Kingdom. (2) Garratt, P. J.; Zahler, R. Tetrahedron Lett. 1979, 73. ( 3 ) Bilyard, K. G.; Garratt, P. J.; m e r , R. Synthesis 1980, 389.

unsuccessful, since reaction of the diester with LDA followed by methylation gave a complex mixture of dimethylated and monomethylated derivatives and acidic products. Some support for Scheme I is afforded by the reaction of 1 with ethanal and propanone, in which the lactones 9a,b are the major products. We presume that 9a,b arise by the sequence of reactions shown in Scheme 11. Clearly, if the half-ester is formed by the mechanism outlined in Scheme I, then its formation should be suppressed if the two ester groups were linked together in such a way that intramolecular attack by the monolithiated precursor is precluded. Anhydrides and cyclic carboximides are the two obvious substrates which might have the desired properties of anion stabilization without the possibility of intramolecular interaction. All attempts to generate dilithiated cis-cyclohexane-1,2-dicarboxylic anhydride were unsuccessful, a complex mixture of products being obtained, but some corresponding N-substituted carboximides readily formed dilithiated specie^.^ Formation of Dilithiated 1,2-Carboximides and Their Reaction with Methyl Iodide. Treatment of (4) For related work on 1,2-carboximides see: Garratt, P. J.; Hollowood, F. J. Org. Chem. 1982, 47, 68.

0022-3263/82/1947-4131$01.25/00 1982 American Chemical Society

Bilyard et al.

4732 J. Org. Chem., Vol. 47, No. 24, 1982

Table I. Reaction of Dilithiated Cyclohexane-l,2-dicarboximides and Dilithiated Dimethyl Cyclohexane-l,2-dicarboxylatewith a,w -Dihalides and a,w -Ditosylates dilithiated yield,a species substrate product % ref llc 14a 15a 47 1I C 14b 15a 59 1 14a 16a 71 3 llc 14c 15c 52 1 14c 16c 53 3 llc 14d 15d 27 1 14d 16d 35 3 * Yields refer to isolated material.

N-tert-butyl-cis-cyclohexane-1,2-dicarboximide (loa) with 2 equiv of LDA gave the dilithiated species l l a . The n

OLI

‘b

\

OLI

loa, R = C5(C6H3)3 b, R = CH, C, R = C,H,

l l a , R = Cs(C6H3)3 b, R = CH, c, R = C6H,

w

0

12a, R = CS(C6H3), b. R = CH, c, R = C,H, - 7

13%R = H b, R = CH,

dilithiated nature of 1 l a is substantiated by its chemical reactions and by its 13CNMR spectrum. Reaction of 1 la with methyl iodide gave the dimethylated derivative 12a in 90% isolated yield. The 13C NMR spectrum of 1 l a in hexamethylphosphoric triamide (HMPA) showed signals at 156.7, 70.0, 54.0, 39.3, 31.7, and 30.7 ppm, assigned respectively to C-1, C-2, (3-5, C-3, C-4, and C-6, consistent with a symmetrical dilithiated species. By comparison with the 13C NMR spectrum of the imide loa, C-1 (24.9 ppm) and C-5 (3.3 ppm) have moved upfield in the dilithiated species and C-2 (29.5 ppm), C-3 (14.8 ppm), C-4 (9.4 ppm), and C-6 (2.0 ppm) have moved downfield. These results are best accommodated by structure lla, a lithium 0enolate with a pyrrole type ring, the change in hybridization leading to a large downfield shift of C-2 (rather than the upfield shift expected because of the negative ~ h a r g e ) .Some ~ evidence for the existence of the related phthalimide dianion, prepared by reduction of Nmethylphthalimide with lithium in liquid NH3, has recently been reported.6 The carboximides 10b,c and 13a could also be readily converted into the corresponding dilithiated species, and on reaction with Me1 these gave the corresponding dimethylated products 12b,c and 13b in high yield (>go%). Reaction of l l b with deuterium oxide also gave 1,2-dideuterio-substituted 10b in 95% yield with a deuterium incorporation of ca. 75% by ‘H NMR spectroscopy.’ Annelation Studies with Dilithiated 1,2-Dicarboximides and a,@-Dibromidesand -Ditosylates. The reaction of the dilithiated species l l c with a,w-dibromoalkanes and -ditosylates was investigated in order to com-

As can be seen from Table I, the substitution of the 1,2-dicarboximides for the 1,2-diester did not lead to an increase in yield of the annelated product, although compounds 15 are more readily isolated than lb, being crys-

16a, n = 3 c,n=4 d,n= 5

talline. As is clear from the last section, the low yields with the carboximides cannot be due to the nonformation of the dilithiated species, and the problem now appears to arise from the strain engendered in forming the tricyclo[4.3.n] system. This is borne out by the isolation of monoalkylated products in these reactions. Thus in the reaction of l l c and 14a, compound 17 was also isolated in 13% yield. This product presumably arises from monoalkylation of the dianion followed by dehydrobromination, via either inter- or intramolecular anion exchange (dehydrohalogenation to give 3-bromopropene followed by alkylation is also possible but appears less likely). Very similar results were observed when the dilithiated 4-cyclohexene-l,2-dicarboximide 18 was reacted with a,wOLI

OL,

18

4% ICH2)n

17

19a, n = 3 b,n=4

20

1976,41, 1209.

dibromides. Besides the corresponding annelated produds 19a,b, a monoalkylated analogue of 17 was also obtained with 1,3-dibromopropanewhich was tentatively identified as 20. Annelation Studies of Dilithiated 1,2-Dicarboximides and 1,2-Diesters with w-Bromo Esters. The Dilithiated diester 2 has been shown to react with ethyl 4-bromobutyrate (21b) at -78 “C to give the keto diester 22b.8 The reactions of 2 with ethyl 3-bromopropionate (21a) and ethyl 5-bromopentoate (21c) were investigated under similar conditions, and the results are shown in Table 11. The reaction of a dilithiated acyclic diester, dilithiated diethyl succinate 23, with 21b was also examined and found to give the monocyclic diethyl cyclo-

92, 1396.

(8) Bilyard, K. G.; Ganatt, P. J. Tetrahedron Lett. 1981,22,1755. See also Noire, P. D.; Franck, R. W. Ibid. 1982,23, 1031.

+

X ( C H p,,) X

‘NC~HS

14a, X = Br; n = 3 OLI

llc

b,X=Tos;n=3

c,X=Br;n=4 d,X=Br;n=5

0

15a, n = 3 c,n= 4 d,n=5

pare the results obtained in these reactions with those obtained for the corresponding dilithiated diester^.^ Results from both series are collected in Table I. ~~

(5)See: House, H. 0.; Prabhu, A. V.; Philips, W. V. J . Org.?hem. (6) Flynn, G. A. J. Chem. Soc., Chem. Commun. 1980,862. (7) Relatively low deuterium incorporation is not uncommon when enolate anions are quenched. See: Creger, P. L. J. Am. Chem. SOC.1976,

J. Org. Chem., Vol. 47, No. 24, 1982 4733

Dilithiated Vicinal Diesters

Table 11. Reaction of Dilithiated

21a, n = 2 b,n=3 c,n=4

4-Cyclohexene-l,2-dicarboximide (18), Dilithiated Diethyl Succinate (23), and Dilithiated Dimethyl 4-Cyclohexene-1,2-dicarboxylate (2) with w -Bromo Esters

dilithiated species substrate

0

22a, n = 2 b,n=3 c,n=4

2 2a 2 5a 2 2b 24 25b 2 2c

21a

2 18 2 23 18 2

OEt

product

21a

21b 21b 21b

21c

yield, %

2oa

trace 61 55 13b OC

Based on isolated 2,4-dinitrophenylhydrazone. Total annelated product ca. 40% (see Discussion). Based on nondetection of 2,4-dinitrophenylhydrazone. a

OEt

23

24

hexan-3-one-1,2-dicarboxylate (24) as a mixture of diastereomers in 55% yield (Table The same series of reactions were carried out by using the dilithiated carboximide 18 with 21a and 21b. These results are also reported in Table 11. As can be seen from Table 11, the most successful annelations occurred between ethyl 4-bromobutyrate (21b) and the dilithiated diesters 2 and 23 to give the bicyclo[4.4.0] system 22b and the monocyclic ketone 24. The annelation of the dilithiated carboximide 18 gave a much lower yield of the tricyclo[4.4.3] derivative 25b, but this was accompanied by a larger amount of the annelated but ring-opened compound 26 (Scheme 111). Thus it appears that 25b is unstable under the reaction conditions and that partial opening of the carboximide ring occurs by attack of the ethoxide ion formed in the initial reaction. The 'H NMR spectrum of 26 has a double doublet at 6 3.05 attributable to the ring junction proton vicinal to the carbonyl group. This proton is coupled to the adjacent methylene protons with apparent coupling constants of J = 7 and 2 Hz,but it is not possible to assign the stereochemistry of 26 on this basis since models indicate that in both the cis and trans isomers these couplings should be unequal. The product derived from monoalkylation of 18 was also obtained in 19% yield in this reaction. With ethyl 3-bromopropionate(21a) the dilithiated ester 2 gave a low yield of the annelated compound 22a whereas the dilithiated carboximide 18 gave only monoalkylated products (15%). In the case of ethyl 5-bromopentoate (214, no annelated products could be identified in the reaction with 2. The conditions used for the reaction of 2 with 21a,c are based on the optimized conditions for the reaction of 2 and 21b, and it is possible that conditions could be found to increase the yield of annelated products in these reactions. It is unlikely that a significant yield of 25a could be obtained from the reaction of 18 with 21a as this product is very seriously strained. The reaction of 2 with 21b at ca. 20 "C produced, as was reported briefly elsewhere: a different product which was identified as 31. We suppose that this product occurs because of equilibrium between the dianion and ethyl 4-bromobutyrate to give the corresponding monoanions (Scheme IV). Displacement of bromide ion from the anion of 21b should be facile and lead to ethyl cyclopropanecarboxylate (28). Reaction of the monoanion 27 with 28 with loss of ethoxide gives the @-ketoester 29 which can react with ethoxide to give the enolate anion 30. Intra(9) Interestingly, the 'H NMR spectrum of the 2,4-dinitrophenylhydrazone of 26 suggests that this is largely one stereomer, possibly because of equilibration under the strongly acid conditions of ita formation.

Scheme I11

ti

25b

26

ac::M)

Scheme IV

+

C02Me

Br(CH2)3COZEt

21b

2

\I\COzMe H

V

1

27

F C 0 , E t

+

Br-

28 29

I

V

V

30

31

32

molecular displacement of methoxide and a protropic shift then gives 31. These reactions follow a pattern similar to those between 1 and ethanal or propanone. Compound 31 is readily dehydrogenated to the aromatic lactone 32. Discussion

The carboximides have a clear advantage over the 1,2diesters in that a clean reaction to the dilithiated species

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J. Org. Chem., Vol. 47, No. 24, 1982

Bilyard et al.

can be accomplished without alternative intramolecular reactions of the monolithiated species. However, the carboximides provide their own problems in that the cyclic imide introduces a degree of strain not present in the diesters, and, consequently, a greater proportion of monoalkylated products is formed with the carboximides. Further, in the case of the reaction with w-bromo esters either little reaction occurs or the polycyclic system formed is susceptible to opening of the carboximide ring. In the reaction of the dilithiated esters with aldehydes, ketones, and esters having acidic a-protons, equilibrium can occur. This seems impossible to circumvent in the case of the aldehydes and ketones, condensation appearing to be slower than equilibration at -75 O C . With ethyl 4bromobutyrate equilibration is sufficiently slow at -75 O C for acylation to be observed, but at higher temperatures equilibrium does lead to the formation of other products. We have examined a number of other difunctional compounds as possible precursors in annelation reactions. For these to be useful, lithiation must be reasonably facile and the dilithiated species stable at the temperature at which alkylation or acylation will occur. If the electrophilic reagent contains any sufficiently acidic protons, then the dianion may react as a base rather than as a nucleophile. We have shown in at least one case that the occurrence of such an undesired side reaction may be attenuated by conducting the annelation over a prolonged period at a lower temperature. The anion-stabilizing substituents must also not be too efficient as leaving groups; thus we were unable to dilithiate 1,2-dicyano-4-cyclohexene(33),

33

34

35

which instead underwent a loss of cyanide to give presumably the anion of l-cyano-1,4-cyclohexadiene(34), which methylated to give 5-cyano-5-methyl-1,3-cyclohexadiene (35). N,N'-Dimethyl-N,N'-diphenyl-4-cyclohexene-l,2-dicarboxamidealso failed to dilithiate in the desired manner. A problem with both the 1,2-diesters and the carboximides is that they provide products containing carboxylic functions which are not readily transformed in high yield into other groups. We continue to explore other anion stabilizing groups which would both allow annelation and provide substituents more susceptible to functional group manipulation.

Experimental Section lH NMR spectra were obtained on either a Varian T-60or XL-200 spectrometer in CDC13as the solvent and are reported in 6 units with Me4Sias an internal standard. 13CNMR spectra were obtained on either a Varian CFT-20 or XL-200 spectrometer in CDCl, as the solvent and are reported in 6 units with MelSi as an internal standard. Mass spectra were obtained on a VG7070F spectrometer and IR spectra on a Perkin-Elmer 177 spectrometer. Melting points were taken on a Kofler hot-stage melting point apparatus and are uncorrected. Unless otherwise stated, reactions were worked up by addition of water and extraction with ether. The ethereal layer was washed with water and saturated NaHCO, solution and dried. Solutions of i-PrzNLi

were prepared under Nz by the addition of the appropriate amount of n-BuLi in n-hexane to a 10% excess of i-Pr,NH in THF or THF-HMPA at or below 0 "C. Solvents were purified by standard methods, and those used for lithiation reactions were scrupulously dried. Reaction of the Dilithiated Esters 1 and 2 with MeI. The diester (1mmol) was dissolved in THF (1mL) and the solution added dropwise to a stirred solution of i-Pr2NLi (2.1 mmol) in T H F (5 mL) at -75 "C under N2. The resultant deep yellow solution was stirred for a further 25 min at -75 "C, and then Me1 (0.2 mL, ca 3.2 mmol) was added by using a syringe. Stirring was continued at -75 "C for a further 30 min, and the reaction was allowed to warm to 20 "C and stirred for a further 2 h, by which time the solution had become pale yellow. The solution was cooled to -75 "C, aqueous acetic acid (33%, 1.5 mL) was added, and the reaction mixture was worked up. Removal of the ether gave a yellow oil which on short-path chromatography on silica gel, eluting with EhO/hexane, gave the dimethyl derivative as a colorless oil. 3: 126 mg (55%); mass spectrum, m / e (relative intensity) 229 (M' 1,88), 197 (M' - 31, loo), 168 (M+ - 60,43); 'H NMR b 3.59 (5, 6 H),2.23-1.15 ( ~ , 1 H); 4 13CNMR 6 176.3, 52.0, 50.7, 47.2, 31.3, 20.3, 19.0. 4 147 mg (65%);mass spectrum, m / e (relative intensity) 226 (M+, l),194 (M+ - 32,3), 166 (M' - 60,32); 'H NMR 5.62 (m, 2 H), 3.68 ( 8 , 6 H), 2.73-1.67 (m, 4 H),1.23 (s, 6 H); 13C NMR 6 175.8, 123.3, 51.4, 46.0, 33.0, 19.5. The combined aqueous solutions from the workup were acidified to pH 1 (10 M HCl) and extracted with CHC1, (3 X 30 mL). The organic layers were combined and dried (Na2S04),and the solvent was removed under reduced pressure to give a pale yellow oil. 5: 52 mg (28%); mass spectrum, m / e (relative intensity) 168 (M+- 18,3), 155 (M+ - 31, lo), 140 (M+ - 46,33), 126 (M+- 60, 27), 81 (100);'H NMR [(CD,),CO] 6 9.39 (br s, 1 H), 3.67 (s, 3 H), 3.10-2.67 (m, 2 H), 2.34-1.24 (m, 8 H); I3C NMR 6 179.8, 173.8, 51.3, 42.3, 42.0, 26.0, 25.6, 23.4, 23.3. 6: 41 mg (22%); mass spectrum, m / e (relative intensity) 166 (M+ - 18,2), 153 (M' - 31,5), 138 (M+- 46,14), 124 (M+ - 60, 19), 79 (loo), 'H NMR [(CD,),CO] 6 10.48 (br s, 1 H), 5.73 (br s, 2 H), 3.70 (s, 3 H),'3.35-2.88 (m, 2 H), 2.75-2.22 (m, 4 H); 13C NMR 6 179.0, 173.2, 124.5, 51.3, 39.0, 38.9, 25.1, 24.9. Reaction of t h e Dilithiated Diester 1 with Ethanal. A solution of ethanal (176 mg, 4 mmol) in THF (5 mL) was cooled to -75 "C under N2 To the stirred solution was added by syringe over 5 min a solution of the dilithiated ester 1 [prepared by adding the diester (200 mg, 1 mmol) in dry THF (1 mL) to a stirred solution of i-Pr2NLi (2.1 mmol) in dry THF (3 mL) containing HMPA (0.5 mL) at -75 "C under N2,stirring for 30 min, and then allowing the red solution to warm to 20 "C]. The reaction mixture was allowed to warm to 0 OC and was stirred at that temperature for 1h. The mixture was cooled to -75 "C, aqueous acetic acid (33%, 1.5 mL) was added, and the mixture was worked up. Removal of the solvent under reduced pressure gave a yellow oil which was chromatographed on silica to give some starting diester (ca. 25 mg) and the lactone 9a (150 mg, 71%) as a mixture of stereomem mass spectrum, m / e (relative intensity) 212 (M+,12), 197 (M' - 15,20), 181 (M' - 31,35), 169 (M+- 43,100); H NMR (CC14)6 4.28, 4.15 (9, 1H, J = 7 Hz), 3.73 (s, 3 H), 3.17-2.95 (m, 1 H), 2.33-1.00 (m, 1 H); IR, CHC13, 1770, 1735 cm-'. When the reaction was carried out at 0 "C, mainly starting diester was isolated (55%), and at -30 "C the ratio of ester to lactone was ca. 1:l. Reaction of the Dilithiated Diester 1 with Propanone. Dry propanone (174 mg, 3 mmol) in THF (1mL) was added rapidly to a solution of the diester dianion [prepared from the diester (200 mg,1"01) in THF (1mL) and i-Pr2NLi (2.0 "01) in THF (8 mL) at -75 "C] at -75 "C under N2. The mixture was stirred for 1h at -75 "C, aqueous acetic acid (33%, 1.5 mL) was added, and the mixture was worked up to give a pale yellow oil (195 mg). Separation on a Harrison Chromatotron (silica gel, EhO/hexane) gave the starting diester (52 mg, 26%) and the lactone 9b: 120 mg (53%); mass spectrum, m / e (relative intensity) 226 (M', lo), 211 (M+- 15,25), 195 (M+ - 31,20), 182 (M+- 44,30), 168 (M+ - 58, 100); 'H NMR (CCl,) 6 3.77 (s, 3 H), 3.40-3.13 (m, 1 H), 2.40-0.80 (m, 14 H); IR (CHCl,) 1775, 1735 cm-'.

+

'

Dilithiated Vicinal Diesters

Synthesis of Carboximide loa. A mixture of cis-cyclohexane-1,2-dicarboxylic anhydride (10.0 g, 0.065 mol) and tertbutylamine (5.33 g, 0.073 mol) in glacial acetic acid (100 mL) was heated to reflux for 40 h. After the mixture cooled, water (100 mL) was added and the resulting solution extracted with Et20 (2 x 50 mL). The combined organic layers were worked with aqueous HCl(2 M, 50 mL) and Na2COs(saturated, 50 mL) and dried. The solvent was removed under reduced pressure and the resulting white solid recrystallized from pentane as loa: 10.20 g (75%); mp 54-55 "C; mass spectrum, m / e (relative intensity) 209 (M+, lo), 194 (M+- 15,14), 154 (M' - 55,100); 'H NMR 6 2.80-2.52 (m, 2 H), 1.95-1.18 (m, 17 H); 13CNMR 6 179.5, 56.6, 39.3, 27.5, 23.1, 21.1; 13CNMR (HMPA) 6 181.6, 57.3,40.5, 28.7, 24.5, 22.3. Anal. Calcd for C12Hlg02N:C, 68.87; H, 9.15; N, 6.69. Found C, 68.59; H, 9.19; N, 6.58. Synthesis of Carboximide lob. A mixture of cis-cyclohexane-l,2-dicarboxylic anhydride (5.0 g, 0.0325 mol) and methylammonium hydrochloride (5.0 g, 74 mmol) in glacial acetic acid (50 mL) containing NaOAc (10.0 g) was heated to reflux for 24 h. After cooling, sufficient aqueous Na2C03(saturated) was added to adjust the pH to 8.5, and the reaction was then worked up as for 10a to give lob: 5.10 g (94%); mp 50-51 "C; mass spectrum, m / e (mass spectrum) 167 (M', 75), 152 (M+ - 15,2), 138 (M' - 29, 18), 67 (100); 'H NMR 6 2.97 ( 8 , 3 H), 2.86 (t, 2 H, J = 5 Hz), 2.00-1.62 (m, 4 H), 1.44 (t,4 H, J = 5 Hz);13CNMR 6 178.7,38.7, 23.5, 22.7,20.6. Anal. Calcd for C&Il3O2N C, 64.65; H, 7.84; N, 8.38. Found: C, 64.23; H, 7.96; N, 8.23. Synthesis of Carboximides 13a and 1Oc. A warm solution anhydride (15.2 g, 0.1 mol) of cis-cyclohex-4-ene-1,2-dicarboxylic in glacial acetic acid (50 mL) was added to a solutioin of aniline (9.95 g, 0.107 mol) in glacial acetic acid (50 mL). The mixture was heated to reflux for 18 h, the solution cooled, and water (50 mL) added. A white precipitate was formed which was removed by filtration. The filtrate was treated with water (50 mL), and further precipitation occurred, the precipitate again being collected. This procedure was continued until no more precipitate was obtained. The collected precipitates were combined and dissolved in CHCl, (ca. 150 mL), and the resulting solution was washed with aqueous HCl(4 M, 50 mL) and NaOH (lo%, 50 mL) and dried (Na2S04).The solvent was removed under reduced pressure and the resulting solid recrystallized from CC14/hexane as 13a: white needles; 17.3 g (76%); mp 115-116 "C; mass spectrum, m / e (relative intensity) 227 (M', loo), 198 (M+- 29, 20); 'H NMR 6 7.67-7.13 (m, 5 H), 6.10-5.92 (m, 2 H), 3.4-3.13 (m, 2 H), 3.00-2.03 (m, 4 H); 13CNMR 6 178.8, 131.8, 128.6, 128.1, 127.4, 126.0, 38.8, 23.3. Anal. Calcd for CI4Hl3O2N: C, 73.99; H, 5.77; N, 6.16. Found: C, 73.86; H, 5.74; N, 5.93. Compound 13a (2.0 g) was dissolved in EtOAc/MeOH (3:l) and Pd/C (5%,0.50 g) was added and the mixture stirred under a H2 atmosphere. Removal of the catalyst and evaporation of the solvent gave 1Oc: white crystals; 2.0 g (ca. 100%); mp 129-130 "C; mass spectrum, m / e (relative intensity) 229 (M', loo), 119 (M+ - 110,99); 'H NMR 6 7.35 (m, 5 H), 3.0 (m, 2 H), 2.15-1.70 (m, 4 H), 1.70-1.35 (m, 4 H). Lithiation of the Carboximides loa-c and 13a. The carboximide (1mmol) was dissolved in dry THF (1mL) and added dropwise to a stirred solution of i-Pr2NLi(2.1 mmol) in THF (3 mL) a t -75 "C under N,. The resulting yellow solutions were stirred at -75 "C for 20 min. In the preparation of dilithiated 13a, HMPA (0.5 mL) was added to the i-Pr2NLi solution. Methylation of the Dilithiated Carboximides. Me1 (0.2 mL, ca. 3.2 mmol) was added to the dilithiated carboximide solution (1mmol) at -75 "C from a syringe. The solution was stirred for 30 min at -75 "C and then for 1.5 h at 20 "C, by which time the yellow color was largely discharged. Aqueous acetic acid (33%, 1.5 mL) was added and the mixture worked up to give the dimethylated carboximides 12a-c and 13b. 12a: 205 mg (90%);bp 103-105 "C (0.2 mmHg); mp 32.5-35 "C; mass spectrum, m / e (relative intensity) 237 (M', 13), 222 (M+ - 15, 8), 182 (M+ - 55, 100); 'H NMR 6 1.95-1.2 (m), 1.53 (s, 17 H), 1.07 (s,6 H); I3C NMR 6 183.4,57.1,46.7,32.6, 28.1,21.5,19.7. Anal. Calcd for C14H2302N:C, 70.85; H, 9.77; N, 5.90. Found: C, 70.61; H, 9.55; N, 6.15. 12b 181mg (93%);bp 82-84 "C (0.2 mmHg); mp 29-30.5 "C; mass spectrum, m / e (relative intensity) 195 (M', 8l), 180 (M+ - 15, 31), 110 (100); 'H NMR 6 3.00 (s, 3 H), 2.03-1.33 (m, 8 H),

J. Org. Chem., Vol. 47, No. 24, 1982 4735 1.17 (s, 6 H); 13C NMR 6 182.6, 47.0, 32.7, 24.5, 21.2, 20.0. Anal. Calcd for CllH1702N C, 67.66; H, 8.78; N, 7.17. Found C, 67.32; H, 8.66; N, 7.01. 12c: 223 mg (87%);mp 74-75 "C; mass spectrum, m/e (relative intensity) 257 (M', 97), 243 (M+ - 14, 13), 110 (77); 'H NMR 6 7.25 (m, 5 H), 2.0-1.3 (m, 8 H), 1.24 (s, 6 H). Anal. Calcd for C16Hlg02NC, 74.68; H, 7.44; N, 5.44. Found: c, 74.54; H, 7.45; N, 5.49. 13b 220 mg (86%);mp 83-85 "C; mass spectrum, m / e (relative intensity) 255 (M+, loo), 240 (M' - 15, 50), 226 (M+ - 29, 10); 'H NMR 6 7.60-7.10 (m, 5 H), 6.08-5.85 (m, 2 H), 3.05-2.00 (m, 4 H), 1.35 (s, 6 H); 13C NMR 6 181.6, 132.0, 128.8, 128.3, 126.2, 47.2, 34.0, 20.4. Anal. Calcd for cl6Hl7o2N: C, 75.27; H, 6.71; N, 5.49. Found: C, 74.99; H, 6.73; N, 5.72. Deuteration of Dilithiated Carboximide 1 lb. A mixture of D 2 0 (99.8% D, 1.0 mL) and CH3C02D(99.8% D, 1.0 mL) in T H F (3 mL) was added to a stirred solution of l l b (1mmol) at -75 "C by using a syringe. The mixture was allowed to warm to 20 "C and was stirred for 1.5 h. The workup gave a pale yellow oil which crystallized on standing: 167 mg (99%); mass spectrum, m / e (relative intensity) 169 (M', C9HllD2N02,67), 168 (M', C9H12DN02,53); 'H NMR 6 3.02 (s, 3 H), 2.88 (br t, 0.5 H, J = 6 Hz), 2.13-1.27 (m, 8 H). Reaction of the Dilithiated Carboximides l l c and 18 with a,w-Dibromides and -Ditosylates. A solution of the dibromide or ditosylate (1.2 mmol) was added to a stirred solution of l l c [1.0 mmol; prepared from 1Oc (229 mg, 1 mmol) and i-Pr2NLi (1mmol) in T H F (5 mL) containing HMPA (0.5 mL)] or 18 at -75 "C under N2. The mixture was stirred at -75 "C for 2 h, allowed to warm to 20 "C, and stirred for a further 14 h. Saturated ammonium chloride (10 mL) was added and the mixture extracted with CH2C12(3 X 50 mL). The organic layen were dried (Na2S04), the solvent was removed under reduced pressure, and the residue was chromatographed on silica gel. 15a: 127 mg (47% from 14a); 160 mg (59% from 14b); mp 62-63 "C; mass spectrum, m / e 269 (M+,82), 122 (M+ - 147,100); 'H NMR 6 7.3 (m, 5 H), 2.4-1.2 (m, 14 H). Anal. Calcd for C17Hlg02N:C, 75.81; H, 7.11; N, 5.20. Found: C, 75.84; H, 6.92; N, 5.21. 17: 35 mg (13% from 14a); 32 mg (12% from 14b); mass spectrum, m / e (relative intensity) 269 (100). 15c: 148 mg (52%); mp 144-145 "C; mass spectrum, m / e (relative intensity) 283 (M', 19), 299 (M+- 54,4), 136 (M+ - 147, 23), 83 (100); 'H NMR 6 7.3 (m, 5 H), 1.9-1.2 (m, 16 H). Anal. Calcd for C18H2102NC, 76.30; H, 7.47; N, 4.94. Found C, 75.94, H, 7.50; N, 4.89. 15d 80 mg (27%); mp 88-89 "C; mass spectrum, m / e (relative intensity) 297 (M+,57), 229 (M+ - 68, 100); 'H NMR 6 7.3 (m, 5 H), 2.4-1.0 (m, 18 H). Anal. Calcd for C19H23N02:C, 76.74; H, 7.80; N, 4.71. Found: C, 75.97; H, 7.65; N, 4.78. 19a: 73 mg (27%); mp 66-67 "C; mass spectrum, m/e (relative intensity) 267 (M', go), 224 (M' - 43, 21), 91 (100); 'H NMR 6 7.4 (m, 5 H), 6.03 (m, 2 H), 3.13-1.33 (m, 10 H). 20 37 mg (14%); mp 186-188 "C; mass spectrum, m/e (relative intensity) 267 (M', 94), 148 (100); 'H NMR 6 7.42 (m, 2 H), 7.18 (m, 5 H), 6.50 (m, 1 H), 5.96 (m, 2 H), 2.62 (d, 1 H), 2.2-1.4 (m, 6 H). 19b: 123 mg (43%); mp 130-131 "C; mass spectrum, m / e (relative intensity) 281 (M', loo), 91 (53); 'H NMR 6 7.4 (m, 5 H), 5.90 (m, 2 H), 2.93-1.40 (m, 12 H). Reaction of the Dilithiated Diester 2 with *Bromo Esters. The bromo ester (5 mmol) in THF (10 mL) was added by a motorized syringe pump over 18 h to a stirred solution of 2 (5 mmol) in THF (15 mL) containing HMPA (2.5 mL) at -75 "C under N2. The mixture was then stirred between -60 and -80 "C for 120 h, quenched with aqueous acetic acid (33%, 7.5 mL), and worked up to give an orange oil, 22a. This oil was dissolved in methanol (2 mL) and treated with 2,4-dinitrophenylhydrazine (1.0 g, 5.1 mmol) in methanol (15 mL) containing concentrated HCl(2 mL). The solution was heated to just boiling and cooled to give an orange precipitate which was recrystallized from ethanol as the 2,4-dinitrophenylhydrazoneof 22a: 0.43 g (20%); mp 181-182 "C; mass spectra, m / e (relative intensity) 434.1438 (C19H2208N4 requires m / e 434.1438), 434 (M+,ll),433 (M+- 1, 55), 401 (M+- 33,8), 373 (M+ - 61,56), 91 (100);'H NMR d 9.12 (d, 1 H, J = 3 Hz), 8.34 (dd, 1 H, J = 10, 3 Hz), 7.94 (d, 1 H, J

4736

J. Org. Chem., Vol. 47, No. 24, 1982

= 10Hz), 5.82-5.50(m, 2 H), 3.89(s,3H), 3.79(8, 3 H), 3.44-3.36

(m, 1 H), 2.91-2.22(m, 6 H), 1.74-1.53(m, 2 H). Anal. Calcd for C19H2208N4:C, 52.53;H, 5.10;N, 12.90. Found: C, 52.49; H, 5.18;N, 12.78. For 22c the procedure reported above was carried out on the oil derived from this experiment, but no hydrazone could be isolated. For 22b6trituration of the oil with ether/pentane (1:lv/v, 20 mL) gave a white crystalline precipitate which was removed by filtration and recrystallized from CCl,: 0.81g (61%); mp 103-105 "C; mass spectrum, m / e (relative intensity) 266 (M', 3),234 (M+ - 32,5),206 (M+ - 60,5),147 (100);'H NMR 6 5.58(br s,2H), 3.68(s,3H), 3.66(s,3 H), 2.90-1.68(m, 10 H); 13CNMR 6 204.9, 174.7,170.4,124.2,62.0,52.1,51.5,48.6,35.1,31.0,29.0,28.7, 20.3. Anal. Calcd for C14H18O5: C, 63.15;H, 6.81. Found: C, 63.48;

H, 6.92. Reaction of Dilithiated Diethyl Succinate (23) with Ethyl 4-Bromobutyrate (21b). n-BuLi (35mL, 1.57M, 55 mmol) was added slowly by syringe to a stirred mixture of diisopropylamine (8mL, 65 mmol) in dry T H F (200mL) containing HMPA (25 mL) under N2 at -78 "C. After completion of this addition, diethyl succinate (4.35g, 25 mmol) in T H F (10mL) was added and the stirred mixture maintained at -78 "C for 30 min. Ethyl 4bromobutyrate (5.50 g, 28 "01) in THF (10 mL) was then added via a syringe pump over 1 h and the mixture maintained at -78 "C for 6 days. Saturated NH4Cl solution was then added, the mixture allowed to warm to room temperature, and the organic solvent removed under reduced pressure. The residue was extracted with ether (3 X 200 mL), the combined extracts were washed with water (5 X 50 mL) and dried (Na2S04),and the solvent was removed under reduced pressure to give the crude ketone (4.40g, 75%). Chromatography on silica gel, eluting with CH2C12,gave the ketone 24 as a mixture of diastereomers: 3.25 g (55%); mass spectrum, m / e (relative intensity) 242 (M', l), 197 (M+ - 45,11),123 (M' - 119,100);'H NMR 6 4.20(q,4 H), 3.75 (m, 1 H), 3.50(m, 1 H), 2.30 (m, 2 H), 1.80(m, 4 H), 1.25 (t, 6 H). A sample of 24 was treated with 2,4-dinitrophenylhydrazine in MeOH containing H2S04 to give the 2,4-dinitrophenylhydrazone: mp 137-138 "C; mass spectrum, m / e (relative intensity) 422 (M+,8),376 (M - 46,26),349 (M+- 73,48),303 (M+ - 119,100); 'H NMR 6 11.05(9, 1 H), 9.08(d, 1 H, J = 3 Hz), 8.27 (dd, 1 H, J = 10,3 Hz), 7.80 (d, 1 H, J = 10 Hz), 4.30 (q), 4.18 (9) (4 H), 3.74 (d, 1 H, J = 9.6Hz), 3.15(dt, 1 H, J = 9.6Hz) 2.84 (m, 1 H), 1.61-2.34(m, 5 H), 1.30(dt, 6 H). Anal. Calcd for C18H22N408:C, 51.19;H, 5.25;N, 13.27. Found: C, 50.95, H, 5.20;N, 13.26. Reaction of Dilithiated Carboximide 18 w i t h w-Bromo Esters. A solution of the bromo ester (1 mmol) in THF (5.0 mL) was added by syringe over 50 min to a stirred solution of 18 (1 "01) in THF (5 mL) containing HMPA (0.5 mL) at -78 "C under NP The solution was stirred for 96 h at -78 "C, saturated NH4C1 (20mL) was added, and the mixture was worked up. The resulting solid was chromatographed on silica by eluting with EtOAc/ pentane (2:8to 3:7)to give the separate products which were recrystallized. With Ethyl 3-Bromopropionate. A trace (TLC) of annelated product was formed, and two stereoisomeric monoalkylated compounds isolated 51 mg (15%); 'H NMR 6 7.45(m, 5 H), 6.05 (t, 2 H), 4.20 (4, 2 H), 3.15-2.0(m, 9 H) 1.25 (t, 3 H). With Ethyl 4-Bromobutyrate. 25b: 45 mg (13%); mp 118-119 "C (MeOH); mass spectrum, m / e (relative intensity) 295 (M+, 91),120 (100);'H NMR 6 7.5(m, 5 H),6.1(m, 2 H),3.0-1.5 (m, 10H). Anal. Calcd for C18H17N03:C, 73.20;H, 5.80;N, 74. Found: C, 72.45;H, 5.72;N, 4.63.

Bilyard et al. 26: 90mg (26%); oil; mass spectrum, m / e (relative intensity) 341 (Mf, 18),295 (M+ - 46,100);'H NMR 6 7.50-7.14(m, 5 H), 6.05(m, 2 H), 4.15(4, 2 H), 3.05(dd, 1 H, J = 7,2 Hz), 2.88-2.56 (d, dd, 2 H, J = 16 Hz), 2.4-1.5(m, 8 H), 1.25 (t, 3 H). A monoalkylated, noncyclized fraction was also isolated: 64 mg (19%); mass spectrum, m / e (relative intensity) 341 (26),226 (100);'H NMR 6 7.4( 5 H, m), 5.80(s), 5.94(m, 2 H), 4.0(2H, q), 3.0-1.85(7H, m), 1.74(2H, t), 1.14(2H, m), 1.12(3H, t). Reaction of 2 with Ethyl 4-Bromobutyrate at -20 "C. A solution of 2 (20mmol) in THF (100mL) containing HMPA (10 mL) at -75 "C was added over 20 min to a stirred solution of 21b (3.92g, 20 mmol) in THF (75 mL) at 20 "C under N2. The resulting red solution was stirred at 20 "C for 18 h, aqueous HCl (10M, 30 mL) was added, and the reaction mixture was worked up. The resulting orange oil (ca. 5.0 g) was distilled through a short-path apparatus under reduced pressure to give a fraction with a boiling point of 125-135 "C (0.07mmHg). This solidified and was recrystallized from CCl, as 31: 1.01 g (28%); white needles; mp 122-123 "C; mass spectrum, m / e (relative intensity) 176.0836(calcd for CllH1202m / e 176.0837),176 (M', 32),148 (M+ - 28,7)107 (M+ - 69,100);'H NMR 6 6.00-5.76(m, 2 H), 4.17 (br d, 1 H, J = 8 Hz), 3.34-2.82(m, 4 H), 1.00-0.44(m, 5 H); 13CNMR 6 172.6,160.4,123.9,123.6,121.8,86.6,24.8,21.6, 12.3,1.93;IR, CHCl,, 1745 cm-'. Dehydrogenation of 31. Dichlorodicyanoquinone (48.4mg, 0.213 mmol) was added to a solution of the lactone 31 (25mg, 0.143mmol) in dry benzene (2X 5 mL), and the resulting mixture was stirred and heated under reflux for 8 h. The solvent was removed under reduced pressure, the residue was extracted with ether (2 X 5 mL), and the ethereal extracts were passed through a short column of Florisil. The solvent was removed under reduced pressure from the colorless eluent, and the residue crystallized (Et20/hexane)as 32: 24.5mg (99%); mp 97-99 "C; mass spectrum, m / e (relative intensity) 174.0681 (calcd for CllHlo02m / e 174-0681),174 (M', 17),146 (M+- 28,51),133 (M+ - 41,62),105 (M' - 69,100); 'H NMR 6 7.90(dd, 1 H, J = 8,2.5Hz), 7.75-7.48 (m, 3 H), 4.85(d, 1 H, J = 9 Hz), 1.20-1.00(m, 1 H), 0.85-0.58 (m, 4 H). Anal. Calcd for C11Hlo02:C, 75.84;H, 5.79.Found: C, 75.52;H, 6.01.

Acknowledgment. We thank the Science and Engineering Research Council (UK) for support. K.G.B. was the recipient of an SERC studentship. Registry No.1, 4336-20-3; 1.2Li, 72039-99-7; 2, 7500-55-2; 2.2Li, 83248-47-9; 3, 83248-48-0; 4, 83248-49-1; 5, 7719-08-6; 6,56124-48-2; 9a, 83248-50-4; 9b, 8324&51-5;loa, 83248-52-6; lob, 83248-53-7; lOc, 26491-47-4; 1la, 83248-54-8; llb, 83248-55-9; 1IC,83248-56-0; 12a, 83248-57-1; 12b, 83248-58-2; 12c, 83248-59-3; 13a, 20141-47-3; 13b, 83248-60-6; 14a, 109-64-8; 14b, 40230-73-7; 14c, 110-52-1; 14d, 11124-0;15a, 83248-61-7; 15c, 83248-62-8; 15d, 83248-63-9; 17, 8324864-0;18.2Li, 83248-65-1; 19a, 83248-66-2; 19b, 83248-67-3; 20, 83248-68-4; 21a, 539-74-2; 21b, 2969-81-5; 21c, 14660-52-7; 22a, 83248-69-5; 22a.DNP, 83248-70-8; 22b, 78813-04-4; cis-24,83248-71-9; trans-24, 83248-72-0; 24-DNP, 83248-76-4; 25a, 83248-73-1; 25b, 83248-74-2; 26, 83248-75-3; 31, 78813-02-2; 32, 78813-03-3; cis-cyclohexane-1,2-dicarboxylicanhydride, 13149-00-3; methylammonium hydrochloride, 593-51-1; cis-cyclohex-4-ene-l,2-dicarboxylic anhyaniline, 62-53-3; ethyl 3-[cis-N-phenyl-3a,4,7,7adride, 935-79-5; tetrahydro-7a-phthalimido]propionate,83248-77-5; ethyl 3-[truns-Nphenyl-3a,4,7,7a-tetrahydro-7a-phthalimido]propionate, 83248-78-6; ethyl [N-phenyl-3a,4,7,7a-tetrahydro-7a-phthalimido]propionate, 83248-79-7; ethanal, 75-07-0; propanone, 67-64-1; tert-butylamine, 75-64-9; diethyl succinate, 123-25-1; MeI, 74-88-4; (i-Pr)*NLi,4111-

54-0.